It has previously been demonstrated that virus infected animals progressively lose their ability to respond to interferon induction, see D. A. Stringfellow and L. A. Glasgow, Hyporeactivity of infection: Potential limitation to therapeutic use of interferon-inducing agents, Infect. Immum., 6: 743 (1972); J. E. Osborn and D. N. Medearis, Suppression of Interferon and Antibody and Multiplication of Newcastle Disease Virus in Cytomegalovirus Infected Mice, Proc. Soc. Exp. Biol. Med., 124: 347 (1967); D. A. Stringfellow, Inducer dependent State of Hyporeactivity Created by Infection, 14th Interscience Conf. Antimicrob. Agents Chemother, Abst. 136, (1974) O. A. Holtermann and E. A. Havell, Reduced interferon response in mice congenially infected with lymphocytic-choriomeningitis virus, J. Gen. Viro, 9: 101 (1970) and D. A. Stringfellow et al., Suppressed Response to Interferon Induction in Mice Infected with Encephalomyocarditis, Semliki Forest, A.sub.2 Influenza, Herpes Hominis Type 2 or Murine Cytomegalo Viruses, J. Infect. Dis., 135:540 (1977). Also, animals exposed to repeated doses of various interferon inducers have been reported to develop a hyporeactive interferon response, see Buckler, C. E., DuBuy, H. G., Johnson, M. L., and Baron, S. 1971. Kinetics of serum interferon response in mice after single and multiple injections of Poly I; poly C. Proc. Soc. Exp. Biol. Med. 136: 394-398., Colby, C., and Morgan, M. J. 1971. Interferon induction and action. Annu. Rev. Microbiol. 25:333-360., Ho, M. and Kono, Y. 1965. Tolerance to the induction of interferons by endotoxin and virus. J. Clin. Invest. 44: 1059-1060, Park, J. K. and Baron, S. 1968. Herpetic keratoconjunctivitis therapy with synthetic double-stranded RNA. Science 1628:811-813, Vilcek, J. 1969. Interferon, pp. 42. In Virology Monographs. Springer Verlag. New York., Vilcek, J. and Rada, B. 1962. Studies on an interferon from tickborne encephalitis virus infected cells. III Antiviral action on interferon. Acta. Virol. 6:9-16, Youngner, J. S. and Stinebring, W. R. 1965. Interferon appearance stimulated by endotoxin, bacteria or viruses in mice pretreated with Esherichia coli endotoxin or infected with Mycobacterium tuberculosis. Nature (London) 208:456-458, Stringfellow, D. A. and Glasgow, L. A., tilorone hydrochloride: An oral interferon-inducing agent. Antimicrob. Agents Chemother 2, 73-78. Stringfellow, D. A. comparative interferon inducing and antiviral properties of 2-amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166), tilorone HCL and Poly I:C. 16th Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract 128B-1976.
The use and effect of PGE.sub.1, on the ability of various cells and mice to produce interferon in response to interferon inducers is described by Mecs, I. and Maraz, A. in Advances in the Biosciences, 9:453 (1972) and by Mecs et al. in Acta Microbiologica Academiae Scientiarum Hunqaricae, 21:265 (1974). However, Mecs et al. does not disclose or suggest that the administration of PGE.sub.1 to cells or animals with a hyporeactive interferon response will restore their ability to respond to interferon inducers.
Both naturally occuring prostaglandins and prostaglandin analogs are known in the art. The naturally occuring prostaglandins have the prostanoic acid skeleton, and carbon atom numbering illustrated by Formula I: ##STR1## See Bergstrom, et al. Pharmacol. Rev. 20, 1 (1968) and references cited therein. For example, prostaglandin E.sub.2 (PGE.sub.2) exhibits the following structure: ##STR2##
The term prostaglandin analog herein refers to those compounds structurally related to the prostaglandins (in that they exhibit a cyclopentane, or adjacently homologous cycloalkane, ring and a pair of side chains attached to adjacent carbon atoms of the ring) which retain characteristic biological properties of the prostaglandins. See Bergstrom, cited above. Various structural modifications of the prostaglandins are known to produce useful prostaglandin analogs. For example, the replacement of the carboxy with a hydroxymethyl or aminomethyl is known; substitution of a methyl, ethyl, or fluoro for a hydrogen at, for example, C-2 or C-16, and replacement of a methylene by an oxa or thia at, for example, C-5 is known. Further, partially deoxygenated prostaglandins are known to be useful prostaglandin analogs. Accordingly, 9-deoxy, 11-deoxy, and 15-deoxy-prostaglandins are known. Further, there are known prostaglandin analogs wherein the double bonds of, for example, PGF.sub.2.alpha. are shifted, e.g., cis-4,5-didehydro-PGF.sub.1.alpha., or replaced by triple bonds, e.g., 13,14-didehydro-PGF.sub.2.alpha.. Finally there are known bicyclic large ringed lactones wherein the C-1 carboxyl forms a lactone with a ring or side chain hydroxyl, at C-9, C-11, or C-15.
As used herein, the term prostaglandin-type compound refers to any prostaglandin or prostaglandin-analog including the carboxylate esters and pharmaceutically acceptable salts thereof.
Among the known prostaglandins are those referred to as A-type prostaglandins, E-type prostaglandins, F-type prostaglandins and D-type prostaglandins by those of skill in the art. The A-type prostaglandins, characterized by a double bond between carbon atoms 10 and 11 in the cyclopentane ring and a keto group at the 9 position, include prostaglandin A.sub.1, or PGA.sub.1, prostaglandin A.sub.2 or PGA.sub.2, prostaglandin A.sub.3 or PGA.sub.3, and dihydro prostaglandin A, or dihydro PGA.sub.1. Similarly, the E-type prostaglandins with a keto group at the 9 position include PGE.sub.1, PGE.sub.2, PGE.sub.3, and dihydro PGE.sub.1, while the F-type prostaglandins with hydroxyl groups at the 9 and 11 positions include PGF.sub.1.alpha., PGF.sub.2.alpha., PGF.sub.3.alpha. and dihydro PGF.sub.1.alpha.. The .alpha.-designation shows the configuration of the hydroxyl group at the 9 position in the cyclopentane ring. The D-type prostaglandins characterized by a keto group in the 11 position and an .alpha. hydroxyl group in the 9 position of the cyclopentane ring, include prostaglandin D.sub.1 or PGD.sub.1, prostaglandin D.sub.2 or PGD.sub.2, prostaglandin D.sub.3 or PGD.sub.3 and dihydro prostaglandin D.sub.1 or dihydro PGD.sub.1, and are described in Foss, P. S., Sih, C. J., Takeguchi, C. and Schnoes., H. (1972) Biosynthesis and Chemistry of 9.alpha.,15(S)-Dihydroxy-11-oxo-13-trans-prostenoic Acid. Biochemistry 11, 2271-2277 as well as U.S. Pat. Nos. 3,767,813 and 4,016,184.
As used herein, the term A-type prostaglandin refers to the A-type prostaglandin or any prostaglandin-analog thereof. The term E-type prostaglandin refers to the E-type prostaglandin or any prostaglandin-analog thereof. The term F-type prostaglandin refers to the F-type prostaglandin or any prostaglandin-analog thereof. The term D-type prostaglandin refers to the D-type prostaglandin or any prostaglanin-analog thereof.
Among the A-type, E-type, F-type and D-type prostaglandin compounds to be used according to this invention are the free acid form, the salt form wherein the cation is pharmaceutically acceptable, and the ester form wherein the alcohol portion is alkyl, especially alkyl of one to four carbon atoms, inclusive, more especially methyl or ethyl.